The present invention relates to a medical composition for atrial fibrillation treatment to mammals including human, which includes 1,4-benzothiazepine derivatives. The present invention also relates to a method of treating atrial fibrillation using such derivatives and to the use of such derivatives for producing a medicine for atrial fibrillation treatment.
While atrial fibrillation is not a lethal arrhythmia, its morbidity is significantly high as 0.4 to 0.9% of the entire population,. and its frequency increases with aging. Such arrhythmia raises the risk rate of cerebral infarction up to about five times, and simultaneously deteriorates exercise capacity. Thus, the atrial fibrillation has been further emphasized as critical arrhythmia in conjunction with progressive increasing in elderly population.
Atrial fibrillation may be defined as a state when disordered excitation or activation is occurring frequently and irregularly in a small part of the atrium without harmonious excitation and construction of the entire atrium. Correspondingly, an electrocardiogram indicates waves having a baseline which fluctuates minutely and continuously (so-called xe2x80x9cf wavexe2x80x9d). This abnormal atrial activation is irregularly conducted to the ventricle through the atrio ventricular node. This causes completely irregular contractions in the ventricle, and absolute arrhythmia appears in pulsation. The arrhythmia includes transient (paroxysmal) arrhythmia which frequently occurs and perpetual arrhythmia.
As to their generation mechanism, the xe2x80x9cReentryxe2x80x9d theory and xe2x80x9cEctopic Impulse Generationxe2x80x9d theory have been suggested. However, it has not been achieved to explain all of the mechanism based on a single theory.
The term xe2x80x9cReentryxe2x80x9d means a phenomenon such that once an occurred excitation is conducted through other cardiac regions and then excites the former region again. Once action potential is generated in a single myocardial cell, the resulting stimulation causes depolarization in adjacent cells, and this stimulation is conducted from one cell to another. Generally, myocardial cells are adapted not to be immediately re-excited due to its long refractory period after the action potential has been generated in one myocardial cell, so that the Reentry is not inherently worked out. Thus, it is required to satisfy the following four conditions to realize the Reentry;
(1) Presence of unidirectional block,
(2) Delay of conduction,
(3) Shortening of refractory period,
(4) Presence of Reentry path.
In these conditions, the presence of unidirectional block is most important. That is, if the conduction is bidirectional or both directions of the conduction are blocked, the Reentry cannot be realized. Excessive conduction velocity disenables the re-excitation because the refractory period is not passed over even if the excitation returns to the former region. Thus, the conduction is necessary to be tardy and slow. Further, shortened refractory period is advantageous to facilitate the establishment of the Reentry.
Diseases caused by atrial fibrillation include mitral valve pathology, ischemic heart disease, hypertension, various cardiomyopathies, constrictive pericarditis, and Basedow""s disease. However, it is often the case that underlying diseases are not clear.
As to therapeutic agents for atrial fibrillation, Japanese Patent Laid-Open Publication No. Sho 49-000265 describes benzothiazole derivatives represented by the following formula; 
Japanese Patent Laid-Open Publication No. Sho 63-255278 (European Patent No.285323, U.S. Pat. No. 4,822,793) describes benzazepine derivatives represented by the following formula; 
Japanese Patent Laid-Open Publication No. Hei 04-234386 (European Patent No. 467325, U.S. Pat. No. 5,082,847) describes carbostyril derivatives represented by the following formula; 
and Japanese Patent Laid-Open Publication No. Hei 09-169743 describes hexahydro-1H-1,4-diazepine derivatives represented by the following formula. 
While another publications other than these documents describe various compounds, they do not describe 1,4-benzothiazepine derivatives as in the present invention.
On the other hand, Japanese Patent Laid-Open Publication No. Hei 04-230681 (International Publication No. WO92/12148, European Patent No. 565721, U.S. Pat. No. 5,416,066) describes 1,4-benzothiazepine derivatives or pharmaceutically acceptable salts represented by the following formulas and a manufacturing method thereof. 
[wherein R represents a hydrogen atom or lower alkoxy group having 1 to 3 carbon atoms; R1 represents a hydrogen atom, lower alkoxy group having 1 to 3 carbon atoms, or substituted phenyl group (wherein the substituent is a hydroxyl group or lower alkoxy group having 1 to 3 carbon atoms), 
(wherein R2 represents an acyl group); X represents an oxygen atom or H2; n represents an integer of 1 or 2; and Ph represents a phenyl group.]
According to the Japanese Patent Laid-Open Publication No. Hei 04-230681, it is described that there are two patterns of necrosis [Static cell death (SD) and Kinetic cell death (KD)] in myocardium of cardiac infarction patients and the major cell death in human cardiac infarction is classified into the KD. It is also described that the invented compounds have an excellent KD suppression effect. However, in this document, no description is included which suggests a certain application as therapeutic agents for atrial fibrillation treatment.
It is an object of the present invention to provide a therapeutic agent for atrial fibrillation treatment to mammals including human.
It is another object of the present invention to provide a method of treating atrial fibrillation to mammals including human.
As a result of a continuous research for achieving the above objects, the inventors have found out that a compound represented by the following formula [I] is amazingly excellent in anti-atrial fibrillation effects, and have completed the present invention.
The present invention is directed to a therapeutic agent for atrial fibrillation treatment, comprising a compound represented by the following formula [I] as an active component. The details will be shown as the following (1) to (7).
(1) A medical composition for atrial fibrillation treatment comprising a compound represented by the formula [I]:
Formula [I]
[wherein R1 represents a hydrogen atom or lower alkoxy group; R2 represents a hydrogen atom, lower alkoxy group or phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from a group consisting of a hydroxides group and a lower alkoxy group), 
(wherein R3 represents an acyl group); X represents xe2x80x94COxe2x80x94 or xe2x80x94CH2xe2x80x94, and n represents an integer of 1 or 2.] or salts thereof or prodrugs thereof; and a pharmaceutically acceptable carrier.
(2) A medical composition as defined in the above (1), wherein said compound is consisting of 4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine, salts thereof or prodrugs thereof.
(3) A method of treating atrial fibrillation comprising administering an effective amount of a compound represented by the above formula [I], salts thereof or prodrugs thereof.
(4) A method as defined in the above (3), wherein said compound is consisting of 4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine, salts thereof or prodrugs thereof.
(5) The use of a compound represented by the above formula. [I], salts thereof or prodrugs thereof, for producing a medicine for atrial fibrillation treatment.
(6) The use as defined in the above (5), wherein said compound is consisting of 4-[3-(4-benzylpiperidine-1-yl)propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine, salts thereof or prodrugs thereof.
(7) A commercial package comprising a medical composition as defined in the above (1) or (2) together with the printed matter relating to said medical composition, said instruction describing that said medical composition is useable or to be used for atrial fibrillation treatment.